간질과산화스트레스 - 발작으로인한산화스트레스 아코니타제 (Aconitase) 의비활성 (Inactivation) - 지방과산화 (Lipid peroxidation) DNA 산화 (DNA oxidation) SOD 변이생쥐 (SOD mutant mice)

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1 KISEP Review 대한간질학회지 2004;8( 8(2): ): 간질과산화스트레스 김원섭 Epilepsy and Oxidative Stress Won Seop Kim, M.D. Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, Korea Epilepsy is arising from many molecular and biochemical events. In the underlying mechanisms of epilepsy, oxidative stress plays an important role in seizure-induced brain damage and neuronal death. Also epileptic seizures are noted in mitochondrial diseases with problems in oxidative phosphorylation. So oxidative stress is an important emerging cause of seizure-induced neuronal death as well as a result of epileptic seizure event. J Korean Epilep Soc 2004;82: KEY WORDSEpilepsyOxidative stressneuronal death Mitochondri. 서 론 간질성발작의산화스트레스증거 대한간질학회지 2004;8(2):

2 간질과산화스트레스 - 발작으로인한산화스트레스 아코니타제 (Aconitase) 의비활성 (Inactivation) - 지방과산화 (Lipid peroxidation) DNA 산화 (DNA oxidation) SOD 변이생쥐 (SOD mutant mice) 대한간질학회지 2004;8(2):

3 김원섭 경련에기인한산화세포사망 (Seizure-induced oxidative cell death) - 미토콘드리아질환과간질 Sod2 Sod2 - 결론 대한간질학회지 2004;8(2):

4 간질과산화스트레스 REFERENCES 1. Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochem Biophys Acta 1998;1366: Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem 1992;59: Turrens JF, Freeman BA, Levitt JG, Crapom JD. The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophsys 1982;217: MacGregor DG, Higgins MJ, Jones PA, et al. Acsorbate attenuates the systemic kainate-induced neurotoxicity in the rat hippocampus. Brain Res 1996;727: Sun AY, Cheng Y, Bu Q, Oldfield E. The biochemical mechanisms of the excitotoxicity of kainic acid. Free radical formation. Mol Chem Neuropathol 1992;17: Bruce AJ, Baudry M. Oxygen free radicals in rat limbic structures after kainate-induced seizures. Free Radic Biol Med 1995;18: Tan D, Manchester LC, Reiter RJ, Qi W, Kim SJ, EI-Sokkary GH. Melatonin protects hippocampal neurons in vivo against kainic acidinduced damage in mice. J Neurosci Res 1998;54: Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 2000;101: Rong Y, Doctrow SR, Tocco G, Baudry M. Euk-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc Natl Acad Sci USA 1999;96: Bruce-Keller AJ, Umberger G, McFall R, Mattson MP. Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann Neurol 1999;45: Bindokas VP, Jordan J, Lee CC, Miller RJ. Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci: Official J Soc Neurosci 1996;16: Coyle JT, Puttfarcken P. Oxidative stress glutamate, and neurodegenerative disorders. Science 1993;262: Dugan LL, Sensi SL, Canzoneiro LMT, et al. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-Methyl-D-aspartate. J Neurosci: Official J Soc Neurosci 1995;15: Dykens JA, Stem A, Trenkner E. Mechanism of kainate toxicity to cerebellar neurons in vivo is analogous to reperfusion tissue injury. J Neurochem 1987;49: Lafon-Cazal M, Pietri S, Culcasi M, Bochaert J. NMDA-dependent superoxide production and neurotoxicity. Nature 1993;364: Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO. Requirement for superoxide in excitotoxic cell death. Neuron 1996;16: Flint DH, Tuminello JF, Emptage MH. The inactivation of Fe-5 cluster containing hydrolyases by superoxide. J Biol Chem 1993; 267: Gardner PR, Fridovich I. Inactivation-reactivation of aconitase in Escherichia coli a sensitive measure of superoxide radical. J Biol Chem 1992;267: Gardner PR, Raineri I, Epstein LB, White CW. Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem 1995;270: Gardner PR. Superoxide-driven aconitase Fe-S center cycling. Biosci Res 1997;17: Patel M, Liang LP, Roberts LJ. Enhanced hippocampal F2-isoprostane formation following kainate-induced seizures. J Neurochem 2001;79: Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ. A Series of prostaglandin F2-like compound are produced in vivo in humans by a noncyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA 1990;87: Robers LJ, Morrow JD. Measurement of F(2)-isoprostances as an index of oxidative stress in vivo. Free Radic Biol Med 2000;28: Baran H, Heldt R, Hertting G. Increased prostaglandin formation in rat brain following systemic application of kainic acid. Brain Res 1987;404: Lan J, Henshall DC, Simon RP, Chen J. Formation of base modification 8-hydroxyl-2 -deoxyguanosine and DNA fragmentation following seizures induced by systemic kainic acid in the rat. J Neurochem 2000;74: Marnett LJ, Burcham PC. Enodgenous DNA adducts: potential and paradox. Chem Res Toxicol 1993;6: Shigenaga MK, Park JW, Cundy KC, Gimeno CJ, Ames BN. In vivo DNA damage: measurement of 8-hydroxy-2 deoxyguanosine in DNA and urine by high-performance liquid chromatography with electrochemical detection. Meth Enzymol 1990;186: Giulivi C, Boveris A, Cadenas E. Hydroxyl radical generation during mitochondrial electron transfer and formation of 8-hydroxydeoxyguanosine in mitochondrial DNA. Arch Biochem Biophys 1995; 316: Mecocci P, MacGarvey U, Kaufman AE, et al. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 1993;34: Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 1995;27: McCord JM, Fridovich I. SOD: an enzymatic function for erythrocuprein chemocuprein. J Biol Chem 1969;244: Weisiger RA, Fridovich I. Superoxide dismutase organelle specificity. J Biol Chem 1973;248: Marklund SL. Extra-cellular superoxide dismutase in human tissues and human cell lines. J Clin Investig 1984;74: Kondo T, Sharp FR, Honkaniemi J, Mikawa S, Epstein CJ, Chan PH. DNA fragmentation and prolonged expression of C-Fos, C- Jun, and Hsp70 in kainic acid-induced neuronal cell death in transgenic mice over-expressing human CuZn-superoxide dismutase. J Cerebral Blood Flow Metabol: Official J Int Soc Cerebral Blood Flow Metabol 1997;17: Liang LP, Chang L, Crapo JM, Patel M. Modulation of excitotoxic injury in extra cellular super oxide dismutase mutant mice. Free Radic Biol Med 2001;31(suppl 1):133. Abstract. 36. Hirata H, Cadet JL. Kainate-induced hippocampal DNA damage is attenuated in superoxide dismutase transgenic mice. Brain Res Mol Brain Res 1997;48: Patel M, Liang LP. Exacerbation of kainite-induced excitotoxicity in SOD2 deficient mice. Soc Neurosci 2001; Patel M. Oxidative stress, mitochondrial dysfunction, and epilepsy. Free Radic Res 2002;36: Schauwecker PE, Steward O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci USA 1997;94: Wallace DC, Zheng X, Lott MT, et al. Familial mitochondrial encephalomyopathy (Merrf): genetic, pathophysiological and biochemical characterization of a mitochondrial DNA disease. Cell 1988;55: Shoffner JM, Lott MT. Lezza AMS, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and red-ragged fiber disease (MER- RF) is associated with a mitochondrial DNA Trna (Lys) mutation. 106 대한간질학회지 2004;8(2):

5 김원섭 Cell 1990;61: Cock H, Schapira AHV. Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy. Epilepsia 1999;40: Naviaux RK, Nyhan WL, Barshop BA, et al. Mitochondrial DNA polymerase gamma deficiency and Mtdna depletion in a child with Alpers syndrome. Ann Neurol 1999;45: Balentine JD. Experimental pathology of oxygen toxicity. In: Jobsis FF. Oxygen and Physiological Function. Dallas: Professional Information Library, 1977; Willmore LJ, Sypert GW, Munson JB, Hurd RW. Chronic focal epileptiform discharges induced by injection of iron into rat and cat cortex. Science 1978;200: Zuchora B, Turski WA, Wielosz M, Urbanska EM. Protective effect of adenosine receptor agonists in a new model of epilepsy-seizures evoked by mitochondrial toxin, 3-nitropropionic acid, in mice. Neurosci Lett 2001;305: Jensen FE, Holmes GL, Lombroso CT, Blume HK, Firkusny IR. Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats. Epilepsia 1992;33: Patel MN, Day BJ, Wallace DC, Liang LP. SOD2-deficient mice exhibit spontaneous age-related seizures and increased susceptibility to kainate-induced oxidative damage and apoptosis. Epilepsia 2001;42: Sorensen L, Ekstrand M, Silva JP, et al. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in milon mice. J Neurosci: Official J Soc Neurosci 2001;21: 대한간질학회지 2004;8(2):

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신하영 이두재 조경주등 Kainate 유발간질모델 - - 크레질바이올렛 (cresyl violet) 염색 Kainate 유발간질모델에서의뇌파검사 대상과방법 산소음이온라디칼 (superoxide anion radical, O.- 2 ) 검출 in situ- - 대한간질학 KISEP Original Article 대한간질학회지 2004;8(2):108 8(2):108-115 115 Kainate 유발간질모델에서 Apurinic/Apyrimidinic Endonuclease 의빠른소실과이에따른세포고사 신하영 이두재 조경주 김미애 이용현 허경 김경환 이병인 Rapid Loss of Apurinic/Apyrimidinic Endonuclease

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